This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine dependence. Almost all subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. Pharmacokinetic approaches being studied include slow onset agonist substitution and enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs, but this has never been systematically studied in humans with stimulants. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. One component of this project is systematically evaluating the influence of dose (10, 25, or 50 mg) and infusion duration (10, 30, or 60 sec) on the effects of IV cocaine in experienced cocaine users. Preliminary findings suggest that at least some of cocaine's psychological (e.g., computer-administered visual analogue scales for "craving," "rush") and physiological (e.g., heart rate, blood pressure, cardiac electrical conduction, cerebral blood flow assessed by transcranial Doppler) effects are both dose- and rate- dependent, correlating with cocaine pharmacokinetics. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE),a major cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Preclinical Pharmacology Laboratory and the National Institute on Aging Gerontology Research Center, rats pretreated with BChE had a 50% reduction in motor activity response to an IP cocaine challenge compared to rats pretreated with saline. BChE itself had no effect on motor activity. BChE-treated rats had 400-fold increases in plasma and 3-fold increases in cerebrospinal fluid BChE activity 24 hours after treatment, suggesting the possibility of persisting effects from a single enzyme administration. Further studies are evaluating the dose-response relationship and time course of this BChE effect.